Neurodegenerative diseases currently have few treatments and no cures. This stems from the lack of understanding of the causes of neuron death in neurodegeneration. Recent research focusing on the proteins discovered to accumulate in the brains of patients, including TDP-43 in amyotrophic lateral sclerosis (ALS), has taken research towards understanding the mechanisms that underlie disease. Modeling disease using pathogenic disease proteins has proved useful for identifying potential pathways, interactions and mechanisms involved in neurodegeneration. In this proposal I will study TDP-43, a pathological protein involved in ALS and frontotemporal dementia, both devastating neurodegenerative disorders. Through modeling TDP-43 related disease in yeast and flies, we have identified a novel interaction between TDP-43 and Ataxin-2, a protein mutated in another neurodegenerative disease, spinocerebellar ataxia type 2 (SCA2). We identified mutations in Ataxin-2 as a novel genetic risk factor for ALS, potentially the most common discovered to date. The TDP-43/Ataxin-2 interaction sits poised as a potential pathogenic mechanism that could provide not only knowledge of disease processes, but also as a potential therapeutic target. Therefore, I will first define the domains of Ataxin-2 and TDP-43 required for the proteins to interact with each other. Second, I will determine if mutations in Ataxin-2 affect the pathological signature of TDP-43, which includes downstream biochemical alterations of the protein, to learn if these mutations influence known disease processes. This will involve training in neuropathology and biochemical methods used to analyze human tissue. Lastly, I will examine if mutations in Ataxin-2 contribute to other neurodegenerative diseases related to ALS that also show TDP-43 involvement. This aspect of the proposal will require training in human genetics methods and analyses, as well as histopathological techniques. Our discovery of a role for Ataxin- 2 in ALS via an interaction with TDP-43 opens up many new avenues for investigation. These experiments will expand our knowledge of the TDP-43/Ataxin-2 interaction and, more broadly, give insight into the similarities and differences of mechanisms underlying different related neurodegenerative diseases.